The pro-inflammatory S100A8/9 heterodimer activates immune cells and vascular endothelium, leading to increased leukocyte traffic into psoriatic tissue. Increased leukocyte trafficking in psoriasis results in monocyte infiltration from the blood, macrophage and myeloid dendritic cell differentiation, and increased T cell activation. Upon T cell activation, TNFcc produced by myeloid monocytic cells is increased thereby mediating psoriasis skin changes. We hypothesize that S100A8/A9 acting as a damage associated molecular pattern molecule (DAMP) recruits, activates and differentiates monocytes into psoriatic skin. We further predict that blocking A8/A9 activity or macrophage recruitment to the uninvolved tissue will block the development of the psoriasis phenotype. Given the unique presence of lining macrophages in psoriatic tissue, this proposal seeks to address whether the accumulation and/or activation of macrophages in psoriatic skin is pathogenic and if this is dependent upon S100A8/A9 levels. The function of "lining macrophages" and the state of differentiation of these particular macrophages is of particular interest, as these cells are in juxtaposition not only to T cells arriving from endothelial venules, but also to basal keratinocytes lining the DEJ. We will determine whether S100 proteins mediate activation or differentiation of the spectrum of myeloid monocytic cells (activated monocytes, DC, macrophages) in lesional skin, and if macrophages are necessary for the development of psoriatic lesions using a xenogenic transplant model. We propose the following specific aims: Aim I: To determine whether myeloid monocytic cells in psoriasis skin are activated to an inflammatory state and/or differentiated to macrophages (DEJ lining or vascular) and the role of S100A8/A9 heterodimer in this process. Aim II: Todefine the role of macrophages and S100A8/A9 in a clinicalpsoriasis response, and in a murine xenogenic transplant model of psoriasis. The interplay of T cell cytokines with monocyte/macrophage cytokines and chemokines and the apparent direct effect on keratinocytes suggests a combined pathology that ultimately results in signals that, together with genetic susceptibility, lead to active psoriasis. Interference (i.e., elimination) with any one cellular component of this triad in disease is (and has been) likely to lead to clinical improvement. Therefore, understanding the relationship between these cell types as well as the importance of each component and potential mechanism(s) of action, are critical to increasing our likelihood of developing therapeutic modalities that address the totality of psoriasis.